the sn2 mechanism of nucleophilic -...

The SThe SNN2 Mechanism of 2 Mechanism of NucleophilicNucleophilicSubstitutionSubstitution

Many Many nucleophilic nucleophilic substitutions follow asubstitutions follow asecond-order rate law.second-order rate law.

CHCH33Br + HO Br + HO –– CHCH33OH + Br OH + Br ––

rate = rate = k k [CH[CH33Br] [HO Br] [HO –– ]]

What is the reaction order of each starting material?What is the reaction order of each starting material?

What can you infer on a molecular level?What can you infer on a molecular level?

What is the overall order of reaction?What is the overall order of reaction?

KineticsKinetics

HOHO –– CHCH33BrBr++ HOCHHOCH33 BrBr ––++

one step

concerted

one step

concerted

Bimolecular mechanismBimolecular mechanism

HOHO –– CHCH33BrBr++ HOCHHOCH33 BrBr ––++

one step

concerted

one step

concerted

Bimolecular mechanismBimolecular mechanism

HOHO –– CHCH33BrBr++ HOCHHOCH33 BrBr ––++

one step

concerted

one step

concerted

HOHO CHCH33 BrBrδ −δ − δ −δ −

transition statetransition state

Bimolecular mechanismBimolecular mechanism

Stereochemistry of SStereochemistry of SNN2 Reactions2 Reactions

GeneralizationGeneralization

Nucleophilic substitutions that exhibitsecond-order kinetic behavior arestereospecific and proceed withinversion of configuration.

nucleophile nucleophile attacks carbonattacks carbonfrom side opposite bondfrom side opposite bondto the leaving groupto the leaving group

Inversion of ConfigurationInversion of Configuration

nucleophile nucleophile attacks carbonattacks carbonfrom side opposite bondfrom side opposite bondto the leaving groupto the leaving group

three-dimensionalthree-dimensionalarrangement of bonds inarrangement of bonds inproduct is opposite to product is opposite to that of reactantthat of reactant

Inversion of ConfigurationInversion of ConfigurationInversion of configuration (Walden inversion) in an SN2

reaction is due to back side attack

A A stereospecific stereospecific reaction is one in whichreaction is one in whichstereoisomeric stereoisomeric starting materials givestarting materials givestereoisomeric stereoisomeric products.products.

The reaction of 2-The reaction of 2-bromooctane bromooctane withwith NaOH NaOH (in ethanol-water) is (in ethanol-water) is stereospecificstereospecific..

(+)-2-(+)-2-Bromooctane Bromooctane ((––)-2-)-2-OctanolOctanol

((––)-2-)-2-Bromooctane Bromooctane (+)-2-(+)-2-OctanolOctanol

Stereospecific Stereospecific ReactionReaction

CC

HH

CHCH33

BrBr

CHCH33(CH(CH22))55

CC

HH

CHCH33

HOHO

(CH(CH22))55CHCH33

NaOHNaOH

((SS)-(+)-2-)-(+)-2-BromooctaneBromooctane ((RR)-()-(––)-2-)-2-OctanolOctanol

Stereospecific Stereospecific ReactionReaction

HH BrBr

CHCH33

CHCH22(CH(CH22))44CHCH33

1)1) Draw the Fischer projection formula for (+)-S-2- Draw the Fischer projection formula for (+)-S-2-bromooctanebromooctane..

2)2) Write the Fischer projection of theWrite the Fischer projection of the

( (––)-2-)-2-octanol octanol formed from it by formed from it by nucleophilic nucleophilic substitution substitution

with inversion of configuration.with inversion of configuration.

HOHO HH

CHCH33

CHCH22(CH(CH22))44CHCH33

R- or S- ?R- or S- ?

A conceptual view of SA conceptual view of SNN2 reactions2 reactions

Why does the nucleophile attack from the back side?

::BrBrCC

HH........

––........HOHO

CHCH33(CH(CH22))55

HH33CC

::BrBrCC

HH........

––........HOHO

CC

HH BrBr

δ δ ––........HOHO ::....

.... δ δ ––

CHCH33(CH(CH22))55

HH33CC

CHCH33(CH(CH22))55

CHCH33

::BrBrCC

HH........

––........HOHO

CC

HH BrBr

δ δ ––........HOHO ::....

.... δ δ ––

CC

HH

HOHO........

––........ ::BrBr

CHCH33(CH(CH22))55

HH33CC

(CH(CH22))5 5 CHCH33

CHCH33(CH(CH22))55

CHCH33

CHCH33

StericSteric Effects in S Effects in SNN2 Reactions2 Reactions

The rate of The rate of nucleophilic nucleophilic substitutionsubstitutionby the Sby the SNN2 mechanism is governed2 mechanism is governedby by steric steric effects.effects.

Crowding at the carbon that bears Crowding at the carbon that bears the leaving group slows the rate ofthe leaving group slows the rate ofbimolecular bimolecular nucleophilic nucleophilic substitution.substitution.

Crowding at the Reaction SiteCrowding at the Reaction Site

RBr RBr + + LiI LiI RI + RI + LiBrLiBr

AlkylAlkyl ClassClass RelativeRelativebromidebromide raterate

CHCH33BrBr MethylMethyl 221,000221,000

CHCH33CHCH22BrBr PrimaryPrimary 1,3501,350

(CH(CH33))22CHBrCHBr SecondarySecondary 11

(CH(CH33))33CBrCBr TertiaryTertiary too smalltoo smallto measureto measure

Reactivity toward substitution by the SReactivity toward substitution by the SNN22mechanismmechanism A bulky substituent in the alkyl halide reduces the

reactivity of the alkyl halide: steric hindrance

CHCH33BrBr

CHCH33CHCH22BrBr

(CH(CH33))22CHBrCHBr

(CH(CH33))33CBrCBr

Decreasing SDecreasing SNN2 Reactivity2 Reactivity

CHCH33BrBr

CHCH33CHCH22BrBr

(CH(CH33))22CHBrCHBr

(CH(CH33))33CBrCBr

Decreasing SDecreasing SNN2 Reactivity2 Reactivity

Reaction coordinate diagrams for (a) the SN2 reaction of methyl bromide and (b) an SN2 reaction of a sterically

hindered alkyl bromide

The rate of The rate of nucleophilic nucleophilic substitutionsubstitutionby the Sby the SNN2 mechanism is governed2 mechanism is governedby by steric steric effects.effects.

Crowding at the carbon adjacentCrowding at the carbon adjacentto the one that bears the leaving groupto the one that bears the leaving groupalso slows the rate of bimolecularalso slows the rate of bimolecularnucleophilic nucleophilic substitution, but the substitution, but the effect is smaller.effect is smaller.

Crowding Adjacent to the Reaction SiteCrowding Adjacent to the Reaction Site

RBr RBr + + LiI LiI RI + RI + LiBrLiBr

AlkylAlkyl StructureStructure RelativeRelativebromidebromide raterate

EthylEthyl CHCH33CHCH22BrBr 1.01.0

PropylPropyl CHCH33CHCH22CHCH22BrBr 0.80.8

IsobutylIsobutyl (CH(CH33))22CHCHCHCH22BrBr 0.0360.036

NeopentylNeopentyl (CH(CH33))33CCHCCH22BrBr 0.000020.00002

Effect of chain branching on rate of SEffect of chain branching on rate of SNN22substitutionsubstitution